Evaluation of the pharmacokinetic interaction between diazepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers.
The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.
Hussey
E K
EK
University of North Carolina, School of Pharmacy, Chapel Hill 27599.
Dukes
G E
GE
Messenheimer
J A
JA
Brouwer
K L
KL
Donn
K H
KH
Krol
T F
TF
Hak
L J
LJ
D000328:Adult; D003975:Diazepam / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004562:Electrocardiography; D006801:Humans; D008297:Male; D010672:Phenytoin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011485:Protein Binding; D014462:Ultrafiltration
D011355:Prodrugs; D010672:Phenytoin; C043114:fosphenytoin; D003975:Diazepam